Asthma, COPD and Respiratory Infections Flashcards
What are the primary functions of the respiratory system?
1) O2 in (external environment) for metabolism (cells and tissues)
2) Co2 (from cells) to external environment
What are the phases of respiration?
1) External (Ventilation)
- Ventilation (breathing)
2) Internal (Diffusion, Transport, Diffusion)
- Pulmonary gas exchange
- Gas transport
- Systemic gas exchange
3) Cellular
- Metabolism
What is external respiration?
Ventilation (breathing) ≈ air moved into/out of lungs in GE from atmosphere to alveoli - Respiration rate regulated to balance removal of CO2 (metabolic waste) and O2 and (from the external environment)
What is the internal phase of respiration?
Pulmonary GE + Gas transport + Systemic gas exchange
What is the hierarchical structure of bronchioles and alveoli?
Trachea —> 1º bronchi —> 2º bronchi —> 3º bronchi —> bronchioles —> Respiratory bronchioles —> Alveolar ducts —> Alveoli sacs
What is the role of the alveoli? How does the structure of alveoli relate to function?
Site of gas exchange between air in the lung and blood ≈ pulmonary gaseous exchange and gas transport - Thin wall (one-cell thick + not muscular) + large surface area ≈ 250um diameter ≈ surrounded by pulmonary capillaries (short gap ≈ 0.2um) ≈ excellent diffusion
What is the equation which relates to diffusion and could explain why gas exchange is so efficient at the alveoli?
Fick’s Law ≈
Q = D A (P2-P1) / L
- D: diffusion co-efficient
- A: Surface Area
- (P2-P1): Partial pressure difference
- L: Wall thickness
What are alveolar membranes composed of?
1) Type I Cells
• Simple squamous epithelia
2) Type II Cells
• Septal cells
• Surfactant secretin cells
• Microvilli
3) Alveolar Dust Cells
• Migrating macrophages
4) Pores of Kohn
• Collateral airflow between alveoli
• Variable number increases in ventilated areas
How do you derive the diffusion co-efficient in pulmonary respiration?
Diffusion coefficient derived from membrane permeability and molecular weight of diffusing substance
What properties of the lung confer stretch?
1) Compliance
• ∆V/∆P
• Stretched easily with small transmural pressure gradient
Condition
• Emphysema: Destruction of Type II pneumocytes, collagen, elastin increased compliance and reduced elasticity increased FRC + lung volume (TLC) increases due to problem getting air out
2) Elasticity
• Elastic recoil recoil post-stretch quiet expiration
Condition
• Fibrosis: CT and collagen deposition reduced elasticity and restrictive disease reduced FRC and lung volume (TLC) reduces
What does elastic recoil and compliance depend on? What does elastic recoil and compliance depend on?
- Fluid in alveoli: H-bonds surface tension alveoli inwards
- Elastin fibers: recoil + compliance
What is La Place’s Law when applied to the alveoli?
What would a small alveolus experiencing an increase in pressure cause?
P = 2T/r ;
T = PR/2
La Place’s Law applied to alveoli: Smaller alveolus ≈small smaller radius ≈ reduced denominator ≈ increase 2T:r ≈ increase P ≈ increase % of alveolar collapse
What would occur if two alveoli of unequal size connected by an airway in the absence of surfactant?
Without surfactant ≈ alveolus has same surface tension ≈ radius is greater in b > a ≈ reduced radius means a (P = 2T/r) > b (P = 2T/r) ≈ greater pressure in alveoli a ≈ smaller one increase % collapse
Does the unequal size of alveoli lead to atelectasis in real life and why or why not?
Collapsing forces mitigated by surfactant + surrounding alveoli ≈ avoid atelectasis
1) Surfactant: Reduce surface tension in smaller alveoli
2) Surrounding alveoli: Alveoli begins collapsing, surrounding alveoli resist collapse due to own elasticity ≈ interdependence
What is the relevance of pulmonary surfactant in the premature babies?
Premature neonates (under 7 months ≈ 28 weeks) ≈ underdeveloped type II pneumocytes ≈ pulmonary surfactant ≈ respiratory effort to inflate non-compliant lungs + lungs collapse in expiration≈ may die of exhaustion + hypoxia
What three pressures are of relevance in ventilation?
- Atmospheric: Pressure from atmosphere –> 760mmHg
- Intra-alveolar Pressure: Pressure in alveoli –> 760mmHg
- Intrapleural Pressure: Pressure in pleural sac (outside lungs within thoracic cavity –> 756mmHg
What is the transmural pressure gradient across the thoracic wall?
Atmospheric - intrapleural pressure
What is the transmural pressure gradient across the lung wall?
Intra-alveolar pressure - intrapleural pressure
What are the muscles of ventilation divided into and why?
1) Inspiration: Contract (Inspiration) + Passive expiration
• Diaphragm
• External intercostal muscles
2) Accessory Muscles of Inspiration
• Sternocleidomastoid
• Scalenus
3) Active Expiration Muscles
• Internal intercostal muscles
• Abdominal muscles
How does respiration occur?
1) Contraction of external intercostal muscles ≈ ribs elevated ≈ up and out ≈increase lateral thoracic cavity diameter ≈reduce pressure ≈ air in
2) Contraction of diaphragm ≈ increase vertical (superoinferior) diameter
What is the process (steps) of inspiration?
- Contraction of diaphragm + external intercostal muscles
- Chest wall and lungs stretched + ribs up and out
- Increased size –> increased volume –> intra-alveolar pressure falls –> Boyle’s Law
- Air enters lungs down pressure gradient until intra-alveolar pressure
What is the process (steps) of inspiration?
- Contraction of diaphragm + external intercostal muscles
- Chest wall and lungs stretched + ribs up and out
- Increased size –> increased volume –> intra-alveolar pressure falls –> Boyle’s Law
- Air enters lungs down pressure gradient until intra-alveolar pressure
What is the process of expiration?
- Relaxation of inspiratory muscles –> passive
- Chest wall + stretched lungs recoil –> return to pre-inspiratory size due to elastic properties
- Intra-alveolar pressure rises as molecules contained in smaller volume
- Air leaves lungs down pressure gradient until intra-alveolar pressure –> atmospheric pressure
State the equation for Boyle’s Law.
P1 V1 = P2 V2
What pathology may alter the transmural pressure gradient and how?
Pneumothorax (air in pleural space) ≈ Spontaneous or Traumatic pneumothorax ≈ intrapleural pressure increases = lung = reduce transmural pressure gradient across lung wall ≈ collapsed lung which fails to inflate due to changes in pressure
How do you determine the lung volume of a patient?
Spirometry
List the values produced by a spirometer, present on a spirogram.
- TV = 0.5L
- IRV = 3L
- IC (TV + IRV) = 3.5L
- ERV = 1L
- RV = 1.2L
- FRC (ERV + RV) = 2.2L
- VC (IC + ERV) = 4.5L
- TLC (IC + FRC) = 5.7L
What is the IRV?
TLC - (TV+ ERV + RV)
What is IC?
TV + IRV
What is VC?
IRV + TV + ERV
What is RV?
TLC - (IRV + TV + ERV)
OR
FRC - ERV
What is FRC?
TV + ERV
In a restrictive lung disease, what may occur in ventilation?
Restrictive lung disease ≈ reduced inspiration ≈ reduced inspiratory volume ≈ reduced VC + reduced TLC + reduced IRV
Describe the changes seen in lung capacity in restrictive lung disease. State examples of restrictive lung diseases which may cause this.
Restrictive Lung Diseases (Sarcoidosis, Asbestosis, Pulmonary fibrosis)
• Reduced compliance ≈ reduced inspiration ≈ reduced inspiratory volume ≈ reduced VC + reduced TLC + reduced IRV
• FEV/FVC < 0.7
Describe the changes seen in lung capacity in obstructive lung disease. State examples of restrictive lung diseases which may cause this.
Obstructive Lung Diseases (COPD, asthma, bronchiectasis, bronchitis)
• Reduced elasticity ≈ reduced expiration ≈ reduced expiratory volume ≈ increased TLC due to increased RV
• FEV/FVC «< 0.7
What is dead space?
Not all inspired air gets to alveoli and partakes in gas exchange thus part remains in conducting airways where no gas exchange occurs ≈ anatomical dead space ≈ airway dead space ≈ 150mL ≈ volume of conducting airways
What is the amount involved in tidal volume?
500mL
How much of the amount of air in each breath (tidal volume) participates in gas exchange and why?
500mL breathed per tidal volume but only 350mL reaches site of gas exchange
What is expected regarding dead space and physiological or anatomical in patients with lung pathology?
Volume of physiological dead space likely to be higher in subjects with lung disease
What is the difference between pulmonary and alveolar ventilation? Give the equation for each.
Pulmonary Ventilation
• Volume of air breathed in and out in 1 minute
- PV = TV x RF
- 6L/min = 500mL x 12bpm
Alveolar Ventilation
• Volume of air exchanged between atmosphere and alveoli per minute
- AV = (TV-DS) x RF
- 4.2L/min = (500-150mL) x 12bpm
How is PV affected by increased TV?
Increase pulmonary ventilation
How is PV affected by increased RF?
Increase pulmonary ventilation
How is AV affected by increased TV?
Increase alveolar ventilation
What would occur if DS increased and TV stayed the same with regards to AV?
Alveolar ventilation would decrease
What yields a greater proportional increase in alveolar ventilation, increasing RF or TV (if DS remains constant)?
Increasing tidal volume
List the mucosal tissues of the human body.
- Conjunctiva
- Respiratory tract: Oral/Sinus/Middle ear/Trachea/Lungs
- GI tract: Oesophagus/Stomach/Intestine
- Urogenital tract: Kidney/Ureter/Uretus/Bladder/Vagina
- Mammary gland
What are mucosal membranes?
Epithelial layers line organs/surfaces exposed to external world ≈ delicate and protected on external mucosal surfaces (mucous secretions, AMPs and dimeric IgA) + submucosal layer (lamina propria ≈ loose CT)
How does IgA protect mucosal surfaces/membranes and give an example of where this happens?
- Plasma cells secrete dimeric IgA
- IgA binds BL surface @ PIgR (polymeric Ig Receptor)
- Endocytosis
- Transcytosis apical
- Release of IgA at apical epithelial cell
List the immune cells of the sub-epithelial lamina propria and when would they be involved?
- Innate Lymphoid Cells: Direct response
- Mast cells: IgE
- Eosinophils: IgE
- Macrophages: Phagocytosis and APC
- Dendritic cells: APC
- T lymphocytes: Memory
- Plasma Cells: IgA, IgG, IgM and IgE
- Mucosa Associated Lymphoid Tissue (MALT): upregulation iMALT
What is the micro-anatomical structure of the respiratory mucosa?
1) Airway Surface Liquid
• Gel layer
• Periciliary fluid layer
• Cilia
2) Epithelium • Cuboidal epithelial layers • Goblet cells • Basal cells • Basement membrane
3) Lamina Propria • Smooth muscle • Connective tissue • Blood vessels • Lymph vessels
4) Cartilaginous Layer
• Cartilage
What is MALT?
- Mucosal Associated Lymphoid Tissue (MALT) = accumulation of lymphoid tissue ordered by lymphoid follicles and germinal centers can be upregulated
- Submucosal dendritic cells carry processed antigen to MALT/BALT –> present to Th2 lymphocytes –> IL-4, IL-5, IL-13 –> Eosinophils –> IgA, IgG, IgE –> hypersensitivity
What is BALT? What are the two types and their features?
- Bronchial associated lymphoid tissue = BALT
- iBALT (inducible) vs cBALT (constitutive)
iBALT
• Upregulated
• Less ordered
• Intraepithelial lymphocytes, lymphoid follicle and marginal T cell zone
cBALT
• Constitutive
• Ordered
• Regional lymph node with defined areas: Paracortical region (T) and 1º lymphoid follicle (B) and medulla
What are the distinctive features of the mucosal immune system? How may these be divided up?
1) Anatomical Features
• Mucosal vs Lymphoid tissues
• Discrete compartments of diffuse lymphoid tissue vs organised structures: Peyer’s Patches, Isolated lymphoid follicles and tonsils
• Specialised antigen-uptake: M cells –> Peyer’s Patches; IgA via PIgR
2) Effector Mechanisms
• T cells
• IgA secretion
• Microbiota
3) Immunoregulatory Environment
• Down-regulation of immune responses
• Up-regulation of immune responses
• Inhibitory macrophages and tolerance-inducing dendritic cells
How is a foreign allergen detected by a B cell?
Specific soluble antigen binds Naive B cells and travels in circulation to lymph nodes ≈ present processed antigen to T follicular helper cells (CD4+ T helper cells) in MHC Class II molecules ≈Activated T follicular helper cell recognises specific antigenic peptide with MHC class II ≈ cytokine secretion (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) ≈ mediate B cell proliferation (of B cell with that BCR) and class switching ≈ plasmablasts form 1º focus ≈ further differentiation proceed to germinal centre ≈ memory cells or antibody-secreting
What antibody mediates asthma?
Asthma is an IgE-mediated lower respiratory allergic reaction ≈ hypersensitivity reaction (Type I)
What are the common stimuli for asthma? Route of entry?
Stimuli:
- Dander (cat)
- Pollens
- HDM
Route of entry:
- Respiratory tract inhalation ≈ contact with mucosal lining of lower airways
List 4 pathophysiological responses to allergens in asthma.
Response: - Bronchial constriction (C) - Increased mucus production (M) - Airway inflammation (I) - Bronchial hyper-reactivity (H) Mnemonic: CHIM
What is allergic asthma?
Reversible airway inflammation with heterogeneous aetiology: allergens (foreign antigens that cause hypersensitivity: plant, fungal, HDM, Der p 1, cat dander, cockroach…)–> activation of submucosal mast cells and basophils of LRT –> degranulation ≈ bronchial constriction + increased mucous secretion –> wheeze, dyspnoea, tightness, cough and variable expiratory airflow limitation
List 3 common types of asthma.
- Allergic
- Exercise-induced
- Neutrophil predominant
What is atopy?
Genetic tendency to produce IgE to common environmental proteins (allergens) to mediate a hypersensitivity reaction, developing classic allergic diseases: atopic dermatitis, allergic rhinitis and asthma
List the atopic triad.
- Dermatitis
- Allergic Rhinitis
- Allergic Asthma
List the three hallmarks of asthma.
- Reversible airway inflammation of heterogeneous origin
- Sx: Wheeze, SOB, Tightness, Cough
- Variable expiratory airflow limitation
Describe the pathogenesis of allergic asthma.
Allergens (HDM, dander, cockroaches, pollen, mold) enters respiratory tract –> phagocytosis by dendritic cells –> taken to a naïve T-lymphocyte in the Paracortical area of lymph node –> APC to mediate Th-2 response –> IL-4, IL-5, IL-9, IL-13 –> Mast cell and Eosinophil degranulation via IgE –> Inflammatory mediators released –> Mucous production; Bronchial inflammation; Bronchoconstriction; Hypersensitivity of airways
List categories of substances produced by mast cells in response to allergen uptake. Outline their actions.
Enzymes: Remodel CT (layer 4) • Tryptase • Chymase • Cathepsin G • Carboxypeptidase
Toxic mediator: Toxic to parasites; Increase vascular permeability; Anticoagulation; Smooth muscle contraction
• Heparin
• Histamine
Cytokines: Inflammation; Cytokine production; Promote eosinophil and innate immune cell production
• IL-4
• IL-5
• IL-13
Chemokines: Chemoattractant for monocyte, macrophages and neutrophils
• CCL3
• CXCL9
Lipid Mediator: SMC contraction; Increased vascular permeability; Stimulate mucous permeability; Bronchoconstriction ||| Attract leukocytes; amplify production of lipid mediators; activate platelets • PDG2 • PDGE2 • LTC4 • LTD4 • LTE4 • Platelet-activating factors (PAF)
Outline the transition to chronic severe asthma.
- Inhaled allergens mediate specific IgE allergic reactions
- Persistent allergens (PAMPs) activate epithelial TLRs
- Epithelium secretes IL-25 and IL-33*
- Activation of ILC Type 2 in submucosal tissue
- ILC Type 2 IL-4, IL-5, IL-13 ≈ enhance Th2 and IgE response
- Increased vascular permeability + chemoattraction: mast cell degranulation + chemokines attract innate immune cells
- Hyper-reactivity driving IgE and other mediators of inflammation
- Resultant pathological changes: Irreversible airway damage and remodeling
List the indications for requesting a CXR.
- Dyspnea
- Acute Chest Pain
- Chronic cough (6 weeks
List the benefits of a CXR.
- Quick
- Accessible
- Identify range of pathologies
List the limitations of a CXR.
- Modest radiation dose
* Insensitive for causes of pathology
Outline the two views of an XR.
- Anteroposterior: XR from front to back
* Posteroanterior: XR from back to front
List the densities seen on an XR.
- Air
- Fat
- Water (soft tissues)
- Bone
- Metal
What factors contribute to a radiological appearance?
- Biologic density
- Thickness of object
- Density of material surrounding it
What is Silhouette sign?
- Object in close contact with material of same density ≈ borders obliterated ≈ difficult to distinguish.
- Usually material more radiopaque with object appearing radiolucent and outline accentuated
What is Summation on an XR?
- Object of same radiographic density overlap but not in contact ≈ summation
- Summation density
What are Mach Bands on an XR?
• Adjacent areas of differing contrast ≈ edge enhancement ≈ accentuation + artifactitious difference in radiographic density between two areas
i) Positive (white) Mach Bands
ii) Negative (black) Mach Bands
List 3 phenomena seen on an XR at times.
1) Silhouette Sign
2) Summation
3) Mach bands
What is the crude approach for CXR Interpretation?
1) ID + Orientation • Who • What: Orientation • Where • Why • When
- Rotation: Sternal end of clavicle equidistant
- Inspiration: Diaphragm at 10-11 posterior ribs on left
- Penetration: IVD of mid-thoracic spine visible
2) Summary • Cardiac monitor wires • Oxygen • Oxygen mask • NG tube • ETT • Venous lines - IJV: trace line from arm to axilla to SVC to heart and tip of line at cavoatrial junction - PICC: trace line from insertion (internal jugular or subclavian vein) towards heart ≈ cavoatrial junction • Cardiac devices • Intercostal catheters
3) Airways • Trachea position: Deviation? • Paratracheal masses • Carina: < 100º • Bronchi: Narrowed or Dilated
4) Breathing • Breathing: S approach in lung field • Lung volume: 10 ribs bilaterally • Zones: Symmetry, Density • Angles: Costophrenic recess (@ Costophrenic angle) and Costomediastinal recess • Cardiac borders: L + R
5) Circulation • Position • Size • Shape • Width • Hila: Position; shape; density
6) Disability
• Ribs
• Clavicles + shoulders
• Vertebral bodies: rectangular, space, x2 pedicles and disc space
7) Everything Else • Gas under diaphragm (pneumoperitoneum) • Subcutaneous emphysema • Hiatus hernia • Absent breast shadow • Lung apexes clear • Lung pathology behind liver
What is the primary function of pulmonary circulation?
Conduit for carrying deoxygenated blood from rest of body via IVC + SVC into RA and out of RV via pulmonary arteries to lung parenchyma to be oxygenated via diffusion then carry oxygenated blood from lung parenchyma (alveoli) to left atrium via pulmonary veins
List the functions of pulmonary circulation.
- Blood transport
- Protection from thrombi and emboli
- Metabolism of vasoactive hormones: ACE; Inactivate BK, Serotonin, PGE1, PGE2, PGF2a; PGA1 and PGA2 pass through unaltered
- Blood reservoir
Compare the haemodynamic features of systemic and pulmonary circulations.
1) Pulmonary Circulation: • Low pressure ≈ 15mmHg • High flow • Low resistance • Mesh-like capillaries • Thin-walled, compliant arteries and veins
2) Systemic Circulation: • High pressure ≈ 120mmHg or MAP = 93mmHg • High flow • High resistance • Parallel capillaries
How does pulmonary vascular resistance change with cardiac output changes? Why do these changes occur?
• Pulmonary vascular resistance falls with increased cardiac output thus inverse relationship
1) Capillary recruitment
• Blood flow increasing ≈ pressure rises ≈ closed vessels open (e.g. apical lung region) ≈ resistance reduced ≈ increase GE + maintain gas exchange
2) Capillary distention
• Blood flow increasing ≈ pressure rises ≈ thin and compliant pulmonary arterioles and capillaries ≈ capillary distention ≈ fall in pulmonary vascular resistance ≈ increase GE + maintain gas exchange
What are the benefits of reducing pulmonary vascular resistance in times of increased cardiac output?
- Maintains adequate gas exchange in times of increased demand: Opposed blood velocity tendency to speed up increased flow rate, maintaining time for pulmonary capillary blood to take up oxygen and dispose of carbon dioxide
- Increase in capillary surface area: Increase capillary surface area ≈ increased gaseous exchange
- Prevent pulmonary oedema: Reducing pulmonary vascular resistance ensures capillary pressure kept low ≈ prevent excess fluid leaking out from pulmonary capillaries
What drives fluid movement generally in the lung?
Fluid movement driven by hydrostatic forces which are normally weaker than colloid pressures allowing net movement of fluid into capillaries however surface tension works against this movement. Thus in diseases where deficient surfactant production occurs may result in pulmonary oedema
How does vascular resistance change at different lung volumes? What are the benefits of the changes in vascular resistance with lung volume?
High lung volume during inspiration ≈ lowering of pleural pressure (more negative) ≈ ∆ transmural pressure ≈ extra-alveolar vessel dilates + alveolar vessels compressed ≈ increase pulmonary resistance
Benefits:
GE increased: Decreased velocity of blood flow ≈ increased time for gas exchange to occur
How do changes in oxygen tension (e.g. Low SpO2) in the lung affect pulmonary vasoconstriction? What is this termed as?
• Low oxygen tension in alveoli (hypoxia) and/or pulmonary blood (hypoxemia) ≈ pulmonary vasoconstriction (hypoxia-induced pulmonary vasoconstriction)
- Hypoxia-induced pulmonary vasoconstriction caused by hypoxia + hypoxemia
- Hypoxia-induced pulmonary vasoconstriction augmented by hypercapnia and acidaemia/acidosis
List drugs causing pulmonary vasodilation.
Adenosine, Acetylcholine, Prostacyclin (PGI2) and isoproterenol
List drugs causing pulmonary vasoconstriction.
Serotonin, norepinephrine, histamine
What are the two types of hypoxia-induced pulmonary vasoconstriction. List the features of each.
Alveolar Hypoxia Types:
1) Regional Hypoxia
• Hypoxia in one region of lung ≈ pulmonary vasoconstriction localised to specific region of lung ≈ diverted from poorly ventilated region ≈ minimises effect of gas exchange
• Little effect on pulmonary arterial pressure
• Alveolar hypoxia no longer exists ≈ vessels dilate and blood flow restored
2) Generalised Hypoxia
• Hypoxia in large region of lung ≈ pulmonary vasoconstriction across lung ≈ pulmonary vascular resistance increases ≈ pulmonary hypertension
• High pulmonary arterial pressure
• Pathophysiological changes: Hypertrophy + Proliferation of smooth muscle cells, narrowing of arterial lumens and change in contractile function + right heart hypertrophy
What is microcirculation? What is its role?
Portion of vascular system comprising arterioles, capillaries and venules where nutrients, water, gases, hormones and waste products exchanged between blood and cells
How is microcirculation regulated?
Regulates blood flow to individual organs, distribution of blood within organs and diffusion distances between organ blood supply and tissues and the exchange of fluid between intravascular and extravascular compartments
1) VSM: Partially constricted ≈ control blood flow
- All micro vessels
- Not capillaries
2) SNS: NE release by SNS ≈ myogenic mechanism intrinsic to smooth muscle
- Change diameter ≈ change vascular resistance
What are the myogenic and metabolic mechanisms contributing to autoregulation of blood flow?
1) Myogenic regulation: ∆ contraction or dilation based on microvascular pressure
• Fast
• High pressure ≈ stretched VSM ≈ activate SAICs contract rapidly
2) Metabolic regulation: Driven by metabolic products
• Increased BMR + low [O2] ≈ vasodilation of arterioles ≈ increased blood flow
List the substances causing vasodilation of arterioles.
- Low O2
- Low ATP
- Increased adenosine
- Increased CO2
- Increased H+
- Increased NO: NO Synthase metabolises L-arginine to NO ≈ activates GC ≈ cGMP
- Lactic Acid
List the substances causing vasoconstriction of arterioles.
• Endothelin
Outline the mechanism by which Endothelin causes vasoconstriction.
Endothelin binds Type B endothelia receptors (GPCR) ≈ PLC ≈ PIP2 ≈ DAG + IP3 ≈ PKC activation + Bind channels ≈ constriction
Which 2 additional forces act in the lung regarding fluid transport/exchange?
- Alveolar surface tension: Pulls inwards ≈ draws fluid into interstitial space
- Alveolar pressure: Compress interstitial space ≈ push fluid out of alveoli
How may the myogenic response be useful in oedema?
• Myogenic arteriolar constriction in negative feedback ≈ lowers arterial pressure ≈ reduced elevation of hydrostatic capillary pressure ≈ reduced risk of oedema
What is the mechanism of flow-mediated vasodilation?
High flow ≈ higher shear stress from blood against endothelial cells ≈ open potassium channels ≈ endothelial cell hyper polarisation ≈ increase calcium entry via electrical gradient ≈ elevated [Ca++] activates NO synthase ≈ increased NO ≈ blood vessels dilate
What is reactive hyperaemia?
Blood flow stopped/reduced by vascular compression ≈ absence of blood ≈ hypoxia (low [O2]) ≈ vasodilatory chemicals accumulate + myogenic stimulation (low intravascular pressure driven) ≈ compression removed ≈ blood flow increased for a few minute as vasodilation following stoppage of flow
What is a capillary. List the 3 types.
• Endothelial tube surrounded by basement membrane composed of dense connective tissue
1) Continuous
• Basal membrane completely surrounds capillary
• Impermeable
2) Fenestrated
• Windows
• Bulk fluid exchange, permeable
3) Discontinuous
• Absent regions of basement membrane
• Exchange of large molecules
What is the difference between diffusion-limited and flow-limited transport? Give examples of molecules which may diffuse by either.
a) Diffusion-limited: Large molecules diffuse more slowly so rely on fenestrated or discontinuous capillaries
b) Flow-limited transport: Small molecules diffuse rapidly and therefore depend on rate of reaching exchange surface
What is oedema? How can it be caused?
Oedema (excessive fluid accumulation in interstitial spaces)
Causes of oedema: • Hypoalbuminemia (< 2.5g/100mL) • Burns: destroy capillary integrity ≈ increased permeability and loss of albumin through damaged vessels • Venous obstruction • Lymph channel obstruction
What is the role of the lymphatic system in preventing oedema?
- Prevent fluid build-up: Mechanically collect fluid from tissue fluid (interstitial fluid) to prevent fluid accumulation and oedema
- Collect proteins: Prevent exudate and water moving out of intravascular compartment to interstitium
- Transport lymphatic fluid: Compression-relaxation cycle facilitating uptake and flow of fluid from interstitium into and down lymphatic channels
What is the effect on net, trans capillary water movement of disease conditions such as heart failure?
In heart failure, heart is failing as a pump ≈ CO reduced + arterial under-filling ≈ reduced renal perfusion≈ reduced GFR ≈ sodium/electrolyte retention in interstitium ≈ water drawn out of intravascular volume into interstitium ≈ net driving force across the capillary ≈ fluid accumulation in the interstitium
What clinical condition can be explained by altered fluid exchange across the pulmonary capillaries?
Pulmonary Oedema
Pulmonary oedema is caused by an abnormal increase in capillary pressure, capillary permeability or alveolar surface tension or a decrease in plasma colloidal osmotic pressure
What are the main pathophysiological causes of pulmonary oedema?
Causes of Pulmonary Oedema:
1) Increased capillary hydrostatic pressure
- E.g. High pulmonary venous pressure from mitral stenosis, left heart failure or heart attack
2) Increased capillary permeability
- Pulmonary vascular injury from oxidant damage, inflammatory reaction or neurogenic shock
- Excess fluid and plasma proteins flooding interstitial paces and alveoli ≈ water drawn by osmosis into interstitial spaces
3) Increased alveolar surface tension
- High surface tension lowering interstitial hydrostatic pressure ≈ increase in capillary fluid entering interstitial space
Two types of pulmonary oedema regarding aetiology?
1) Cardiogenic
2) Non-Cardiogenic
What are the blood flow distribution zones in the lungs?
1) Zone 1: PA > Pa > Pv
• Alveoli exceeds arterial pressure
• Apex of lung
• Occurs only in abnormal conditions whereby alveolar pressure increased (positive pressure ventilation), arterial pressure decreased (gravitational pull whilst standing or takeoff from spacecraft)
2) Zone 2: Pa > PA > Pv
• Gravity causes lungs to be underperfused at apex and over perfused at base
• Blood flow depends on difference between Pa
• Blood flow greater at bottom cf top
3) Zone 3: Pa > Pv > Pa
• Blood flow determined by arterial-venous pressure difference
• Increase in blood flow primarily due to capillary distension
What effect does exercise have regarding the gravitational effects of blood flow in an upright person?
Exercise offsets gravitational effects in upright person: CO increases ≈ increased pulmonary arterial pressure ≈ capillary recruitment + distension in lung’s apex ≈increased blood flow and minimising regional differences in blood flow in lungs
What effect does gravity cause on the regional ventilation and blood flow in the lungs?
Gravity causes V:Q mismatching between ventilation and perfusion in the lungs
What is physiological dead space and how does it arise?
Air on side of alveolar-capillary membrane which does not partake in gaseous exchange ≈ wasted air ≈ physiological dead space
What is physiological shunting and how does it arise?
Blood on alveolar-capillary membrane which does not partake in gaseous exchange ≈ total amount of wasted blood (venous admixture) ≈ physiological shunt
List the investigations relevant for a suspected case of asthma.
• PEF: Absolute values
- PEF Comparison Standardisation for height, age, sex
- PEF Diary: variability; Diurnal variations (Better at night)
• Spirometry: Scalloping of expiratory flow volume loop; FEV1/FEVC < 0.7
- Airway inflammation –> obstruction –> lower FEV but FVC remains similar thus reduced ratio
- Bronchodilator-response spirometry: Inhaled corticosteroid or ß2 agonist yields reversibility (12% improvement in FEV1 or FVC)
- Bronchial provocation tests (BPT): Inhaled Mannitol (indirect) or Methacholine (PD20; Provocation Dose for 20% reduction) (direct) shows FEV1 decreased (15-20%)
- Fractional Expired Nitric Oxide (FeNO) test: Elevated (> 50ppb; normal ≈ 25ppb)
- Approximation of NO produced by eosinophils driven by Th2 response
- FENO has a relatively decent sensitivity (88%) and specificity (79%) however peak flow and spirometry are both more specific (100%) specific but with lower sensitivity
- CXR: Normal; Hyperinflation; Rule out other pathologies
- FBC: Possible eosinophilia, IgE
- Blood culture: Aspergillus
- Bronchoscopy: Normal; Look for structural abnormalities such as tracheomalacia or bronchomalacia
List the signs and symptoms of asthma.
- Wheezing
- Increased work of breathing
- Features of atopy: dermatitis, allergic rhinitis
- History of response to treatment within appropriate time frame
- Dyspnea on exertion
- Expiratory wheeze
- Dry night-time cough
What is a PEF? Comparison types?
Peak expiratory flow rate ≈ PEF in one short, sharp breath
1) PEF Comparison
- Calibrated using diary
- Calibrated using peak flow standardisation for height, age and sex
2) PEF Diary
- Plot PEF changes
- Change with treatments or activities etc
- PEF Diurnal Variation observed
What is spirometry? List two key clinical variables from spirogram.
respiratory investigation assessing lung function measuring inhalation and exhalation, using FEV and FVC to diagnose asthma, COPD and other respiratory conditions
1) FEV = air exhaled in forced breath over 1 second
2) FVC = total amount of air exhaled during FEV test ≈ 6 seconds
What are the interpretive values for spirometry and their meaning? Must you be cautious when interpreting these?
1) Normal: FEV / FVC = 0.7
2) Obstructive: FEV / FVC < 0.7
- More force required to get out full capacity of lungs in expiration≈ lower FEV due to obstruction with FVC staying similar (but can change) ≈ lower ratio
3) Restrictive: FEV/FVC > 0.8
- Lung volumes limited overall ≈ FEV and FVC both decrease ≈ higher ratio
What is a Bronchial Provocation Test? List the two main types and give an example of each.
spirometry to assess baseline function then taking medication or performing exercise to measure lung function via spirometry which tests if airways are sensitive ≈ ∆ lung function
Direct: Mannitol ≈ hypertonic stimulus = osmotic effect releasing inflammatory mediators from mast cells, basophils and eosinophils
Indirect: Methacholine non-selective muscarinic receptor agonist in PSNS ≈ bronchoconstriction (PD20)
Indirect: Exercise
What is meant by PD20 in BPT e.g. in asthma or COPD investigations?
PD20 ≈ Provocation Dose ≈ 20% decline in FEV
List ways you should prepare for a BPT in asthma.
No vigorous exercise 30 mins before - No tight clothing - No smoking 1 hour before - No heavy meal 2 hours before - No alcohol 4 hours before - Withhold medications as per instructed
What is FeNO investigation e.g. in asthma or COPD investigations? Outline the way it works. Evaluate FENO as an investigation - bad or good?
Fractional Exhaled Nitric Oxide ≈ Quantitative, non-invasive investigation involving measurement of exhaled nitric oxide determining how much lung inflammation is present ≈ Th2 cells produce IL-4, IL-5 and IL-13 ≈ driver of inflammation (loosely related) ≈ activated eosinophils produce NO ≈ eosinophilic asthma indicator/ allergic asthma
Normal: 25-50ppb (adults) cf 20-35ppb (children)
FENO has a relatively decent sensitivity (88%) and specificity (79%) however peak flow and spirometry are both more specific (100%) specific but with lower sensitivity
Outline the two main principles for Rx of asthma. List examples for each.
1) Control drivers of inflammation (U-GO-SEA)
• Upper airway disease: sinus/polyps/rhinitis/sinusitis
• GORD
• Obesity
• Smoking
• Exposures: Cigarettes/dusts/occupational/infection
• Allergies/Aero-allergens: Pets/pollen/Aspergillus/HDM
2) Control inflammation • Steroids: Anti-inflammatory • Control upper airway disease • Antacids/anti-reflux • Infection avoidance, vaccination
What is the diagnostic algorithm for asthma comprising of/looking for?
- Recurrent Sx
- Sx variability
- Historical record of variable PEF or FEV1
- Recorded observation of wheeze
- PMHx Atopy
Outline the three categories of asthma risk.
1) High Asthma Risk
• Treatment
• Observe response
2) Intermediate Asthma Risk
• Investigations to check variability (reversibility, PEF charting, BPT) + Eosinophilic inflammation or atopy (FeNO, Blood cultures, Skin-prick IgE)
• Suspected asthma thus wait if asymptomatic or commence treatment if symptomatic
3) Low Asthma Risk
• Other Ddx
• Investigate differentials
What is the stepwise management of pharmacotherapy for asthma? Give the drugs used.
- Low-dose inhaled corticosteroid (ICS): Budesonide (0.25-0.5mg/day nebulized); Fluticasone (100-200mcg/day)
- Leukotriene Receptor Antagonist (LTRA): Monteleukast (4mg PO OD)
- Long-Acting Beta Agonist: Salmeterol (50mcg BD)
- Short-Acting Beta Agonist: Salbutamol (PRN)
- Immunomodulator (Biologics): Omalizumab (Anti-IgE mAb)
What are the different types of severity of asthma and the features and the management of acute severe asthma in adults in hospital?
Severities of Asthma: 1) Acute Severe Features • PEF: 33-50% predicted • Cannot complete sentences in one breath • RR > 25 breaths/min ≈ tachypnoea • HR > 110 beats/min ≈ tachycardia
2) Life-threatening Features • PEF < 33% predicted or best • SpO2 <92% • Silent chest, cyanosis, feeble respiratory effort • Arrhythmia or hypotension • Exhaustion, altered consciousness
Management:
1) Patient Improving
• Maintain treatment but change to 4-6 hourly for drugs
2) No Improvement in 15-30 minutes
• Continue O2 and steroids
• Use continuous nebulisation of salbutamol at 5-10mg/hour
• Continue ipratropium 0.5mg 4-6 hourly until improvement
3) Still not improving
• Discuss with ICU/HDU/ITU and Senior Clinician
• Consider IV MgSO4 (bronchodilator) 1.2-2g over 20 minutes
• Give nebulizer of salbutamol more frequently 15-30 minutes or 10mg per hour via continuous nebulizer
How may biologics target the asthma endotypes?
- Omalizumab: Anti-IgE mAb (Th2-hi asthma)
- Dupilumab: Anti-IL-4 + IL-13 mAb (Th2-hi asthma)
- Azithromycin: Reduces thymic stromal lymphopoeitin (TSLP) of Th2-hi asthma
List the main asthma endotypes and their characteristic features.
Asthma Endotypes:
1) T2-lo asthma
• Th17
• Th1
Cytokines: IL-17, CXCL8, INFy, TNFa
2) Th2-hi asthma
• Th2
• ILC
Cytokines: IL-5, IL-4, IL-13
What is the relation between nasal stimulation and lower bronchi (lower airway) response?
Interaction between upper and lower airway inflammation ≈ nasal stimulation ≈ afferent feedback to CNS ≈ efferent neurone stimulation via PSNS Vagal Nerve ≈ constriction oflower airways
What are the categories of severity for asthma using PEF?
50%-75% ≈ mild
33-50%: moderate
33% > ≈ severe
